1-farnesylacetyl-4-hydroxyalkyl-piperazines

ABSTRACT

N-SUBSTITUTED FARNESYLACETYL PIPERAZINES ARE PREPARED BY ACYLATION OF AN N-SUBSTITUTED PIPERAZINE WITH A FARNESYLACETYL HALIDE. THESE AMIDES EXHIBIT VALUABLE PHARMACOLOGICAL PROPERTIES, I.G. ANTI-ULCEROGENIC, ANTI-BRADYKININ, ANTI-PROTOZOAL AND ANTHELMINTIC.

United States Patent Oifice 3,646,036 l-FARNESYLACETYL-4-HYDROXYALKYL-PIPERAZINES Ivar Laos, Skokie, Ill., assignor to G. D. Searle & Co.,Chicago, Ill.

No Drawing. Filed Mar. 30, 1970, Ser. No. 24,010 Int. Cl. C07d 51/70 US.Cl. 260-268 C 6 Claims ABSTRACT OF THE DISCLOSURE N-substitutedfarnesylacetyl piperazines are prepared by acylation of an N-substitutedpiperazine with a farnesylacetyl halide. These amides exhibit valuablepharma cological properties, e.g. anti-ulcerogenic, anti-bradykinin,anti-protozoal and anthelmintic.

The present invention is concerned with novel derivatives offarnesylacetic acid and, more particularly, withl-farnesylacetyl-4-hydroxyalkyl-piperazines as represented by thefollowing structural formula on, I CH3( 6J=CHCH CH2)a( 3-N NAlk-OHwherein Alk represents a lower alkylene radical possessing at least twocarbon atoms.

The lower alkylene radicals depicted by Alk in the foregoing structuralformula are typified by ethylene, trimethylene, tetramethylene,pentamethylene and the branched chain groups isomeric therewith.

Farnesylacetic acid halides are conveniently utilized as startingmaterials for the manufacture of the compounds of this invention.Reaction with the N-hydroxyalkylpiperazine is readily carried out at lowtemperature. A particularly useful acid halide is farnesylacetylchloride, described by Cardani et al., J. Med. Chem., 6, 457 (1963).Reaction of farnesylacetyl chloride with N-(Z-hydroxyethyl)piperazine,for example, thus afiords l-farnesylacetyl-4- (Z-hydroxyethyl)piperazine.

Equivalent to the amines of this invention are the correspondingnon-toxic acid-addition and quaternary salts thereof as exemplified bythe citrate, maleate, ascorbate, tartrate, succinate, oxalate, lactate,glycolate, gluconate, benzoate, cinnamate, nitrate, hydrochloride,hydrobromide, phosphate, methochloride, methobro-mide, ethochloride,ethobromide, etc.

The compounds of this invention are useful as a result of their valuablepharmacological properties. They are, for example, anti-ulcerogenicagents as is evidenced by their capacity to inhibit ulcer formation inthe Shay rat as reported by Shay et al., Gastroenterology, 5, 43 (1943).Details of the assay utilized to detect that activity are contained inUS. Pat. 3,483,192, issued Dec. 9, 1969. These compounds are alsoanti-protozoal agents in view of their ability to inhibit the growth oforganisms such as Tritrichomonas foetus and anthelmintic agents as isevidenced by their immobilizing action against nematodes such as Turbatrix aceli. The assays used to detect those anti-protozoal andanthelmintic activities are described in detail also in theaforementioned US. Pat. 3,483,192, issued Dec. 9, 1969.

The compounds in this invention possess, in addition, anti-spasmodicactivity as demonstrated by their ability to inhibit bradykinin-inducedcontractions. Details of the assay used for detection of that activityare as follows:

Two Charles River female rats weighing 240-280 grams are treated on eachof two successive days with diethylstilbesterol in order to induce astate of estrus. On the third day the animals are sacrificed and theuteri are removed. A 10 mm. section is taken from one of the uteri3,646,036 Patented Feb. 29, 1972 and suspended in a tissue bathcontaining 1.9 ml. of Tyrodcs solution, prepared as described by Barnesand Eltherington, Drug Dosage in Laboratory Animals, p. 261, Universityof California Press, Berkeley, Calif. (1964). The tissue bath issurrounded by a water jacket maintained at a constant temperature of 30C. The concentration of bradykinin in the tissue bath is then graduallyincreased by successive additions of bradykinin dissolved in Tyrodessolution. The bradykinin solution is defined in the pD, which is the logof the reciprocal of the concentration expressed in mg./ml. \At each ofthe selected bradykinin concentrations, contraction of the uterus ismeasured in mm. by means of an E & M Physiograph used together with anIsotonic Myograph Transducer and Detecting Head. After completion ofthose measurements the tissue is rinsed nine times over a period of 9minutes with fresh Tyrodes solution. The last rinse is kept in the bathand mcg. of the test compound dissolved or suspended in 0.1 ml. ofTyrodes solution is injected into the bath, which consists of 1.9 ml. ofTyrodes solution. After 10 minutes the bradykinin concentration in thebath is again increased as before by the successive additions ofbradykinin dissolved in Tyrodes solution. The contractions at eachconcentration are measured as before and are compared with the controlvalues, i.e. those obtained in the absence of the test compound. Theidentical procedure is then carried out with the 10 mm. section of theuterus taken from the second animal. A compound is considered activeeither if it inhibits by at least 10% the maximum bradykinin-inducedcontraction or if it causes an increase of at least 0.3 pD unit inbradykinin concentration required to effect 50% of the maximumconcentration.

The invention will appear more fully from the examples which follow.These examples are set forth by Way of illustration only and it will beunderstood that the invention is not to be construed as limited therebyeither in spirit or in scope as many modifications both in materials andin methods will be apparent from this disclosure to those skilled in theart. In these examples temperatures are given in degrees centigrade (0C.) and quantities of materials in parts by weight unless otherwisenoted.

EXAMPLE 1 To a solution containing 2.73 parts ofN-(Z-hydroxyethyl)piperazine in 228 parts of butanone, under nitrogenisadded dropwise at 0-5 with stirring over a period of about 10 minutes asolution of 2.83 parts of farnesylacetyl chloride dissolved in 12 partsof butanone. After completion of the addition the reaction mixture isallowed to warm to room temperature, then is heated at the refluxtemperature for about 1 hour. At the end of that reaction period, themixture is cooled and the insoluble material removed by filtration.Removal of the solvent by distillation under reduced pressure affords anoily residue, which is dissolved in benzene. The resulting organicsolution is washed with water until neutral. That solution is dried overanhydrous sodium sulfate and distilled to dryness to aiford1-farnesylacetyl-4-(Z-hydroxyethyl)-piperazme.

The latter amine is dissolved in parts of anhydrous ether and is stirredwhile 1.5 parts by volume of an isopropanolic hydrogen chloride solutiondiluted with 70 parts of anhydrous ether is added. The latter solutioncontains one molecular equivalent of hydrogen chloride. The resultingamine hydrochloride is collected by filtration, then purified bydissolution in isopropyl alcohol followed by precipitation with ether.The resulting precipitate is collected by centrifugation to affordl-farnesylacetyl-4-(2- hydroxyethyDpiperazine hydrochloride. Thiscompound displays nuclear magnetic resonance maxima, indeuterochloroform, at about 98, 102, 120, 142, 200, 242 308 and 365cycles per second and is represented by the following structural formulaEXAMPLE 2 When a solution containing 4.25 parts of farnesylacetylchloride in 20 parts of butanone is allowed to react with a solutioncontaining 4.54 parts of N-(Z-hydroxypropyl) piperazine dissolved in 36parts of butanone according to the procedure described in Example I,there are obtained l-famesylacetyl 4 (2-hydroxypropyl)piperazine and thecorresponding hydrochloride.

EXAMPLE 3 wherein Alk is a lower alkylene group possessing two to sevencarbon atoms.

2. As in claim 1, a compound of the formula 4 wherein Alk is a loweralkylene group possessing either two or three carbon atoms.

3. As in claim 1, a compound of the formula wherein n is either 2 or 3.

4. As in claim 1, the compound which is l-farnesylacetyl-4-Z-hydroxyethyl) piperazine.

5. As in claim 1, the compound which is l-farnesylacetyl-4-(Z-hydroxypropyl) piperazine.

6. As in claim 1, the compound which is 1-farnesy1- acetyl-4-(3-hydroxypropyl piperazine.

References Cited UNITED STATES PATENTS 3,051,710 8/1962 Biel 260-268 C3,244,701 4/1966 Jiirgens et a1 260-268 C 3,385,858 5/1968 Katz 260-268C 3,472,845 10/1969 Thiele 260-268 R 3,480,663 11/1969 Thiele 260-268 C3,513,176 5/1970 Andrews 260-268 X DONALD G. DAUS, Primary Examiner US.Cl. X.R.

